Process for the preparation of 99m Tc, 186 Re or 188 Re nitride complexes usable as radiopharmaceutical products

ABSTRACT

The invention relates to the preparation of complexes of 99m-technetium, 186-rhenium or 188-rhenium usable as radiopharmaceutical products. 
     For this preparation, an oxidized compound of  99m  Tc,  186  Re or  188  Re, e.g. an alkali metal or ammonium perrhenate or pertechnetate, is reacted with a first ligand chosen from the group of substituted or unsubstituted, aliphatic and aromatic phosphenes and polyphosphenes and a second nitrogenous ligand constituted by an ammonium nitride or a pharmaceutically acceptable metal or by a nitrogenous compound having a &gt;N--N&lt; unit, such as hydrazine, a hydrazine derivative, dithiocarbazic acid and dithiocarbazic acid derivatives. 
     The product obtained can be used as it is as a radiopharmaceutical product or can serve as an intermediate for the preparation of other radiopharmaceutical products by exchange reaction with a third ligand, a monoclonal antibody or an antibody fragment.

DESCRIPTION

The present invention relates to a process for the preparation ofcomplexes of a transition metal chosen from among ^(99m) Tc, ¹⁸⁶ Re and¹⁸⁸ Re usable as radiopharmaceutical products or for the synthesis ofnovel radiopharmaceutical products.

More specifically, it relates to the preparation of nitride complexes ofa transition metal M chosen from among 99mTc, ¹⁸⁶ Re and ¹⁸⁸ Re having aportion M.tbd.N in which M represents 99mTc, ¹⁸⁶ Re or ¹⁸⁸ Re.

These radioactive transition metal complexes are usable asradiopharmaceutical products in diagnosis or therapy.

Technetium 99-m complexes are more particularly used for diagnosis,whereas rhenium 186 or 188 complexes are preferably used in therapy.

The radiopharmaceutical products using the radionuclide ^(99m) TC arecompounds which are frequently used in nuclear medicine for diagnosispurposes due to the physical and chemical characteristics of saidradionuclide.

Thus, the latter only gives a gamma emission, has an optimum gammaenergy for the external detection (140 Kev) and has a short physicalhalf-life (6.02 h), which only gives a low irradiation dose to thepatient. In addition, the radionuclide is not expensive and iscommercially available. Finally, the richness of the chemistry oftechnetium makes it possible to obtain a large variety ofradiopharmaceutical products.

Thus, as indicated by E. DEUTSCH et al in Progr. Inorg. Chem.(Australia), vol. 30, pp. 76-106, 1983, technetium can form very variedcomplexes with numerous ligands in oxidation states ranging from VII to-I and coordination numbers from 4 to 9.

Among the numerous complexes of table I of pp. 79-83 of said document,are complexes of 99-Tc in oxidation state V in accordance with theformulas:

    TcN Cl.sub.2 (PPh.sub.3).sub.2

    TcN Cl.sub.2 (PPh.sub.3).sub.3

    TcN Cl.sub.2 (PMe.sub.2 Ph).sub.3

    TcN (S.sub.2 CNEt.sub.2).sub.2

These complexes were prepared by Kaden et al according to the processdescribed in Isotopenpraxis, 1981, 17(4), pp. 174/5, with a view to useas a catalyst in the complex reduction reaction of elementary nitrogeninto ammonia discovered by Volpin and Shur. This process consists ofreacting ⁹⁹ Tc pertechnetate with hydrazine hydrochloride and triphenylphosphine.

For this preparation, use is made of 800 mg of NH₄ ⁹ TcO₄ -and a molarratio of TcO₄ --/NH₂ NH₂, 2HCl of 0.46, i.e. a Tc quantity well abovethat which can be used for the preparation of radiopharmaceuticalproducts or where the quantities involved represent approximately 10 mCiof ^(99m) Tc, i.e. 8.10⁻⁶ mg of 99mTc.

Thus, the source of ^(99m) Tc is the ⁹⁹ Mo-^(99m) Tc generator, whichgenerally supplies an aqueous 0.154M NaCl solution either in the purestate or containing stabilizing agents, in which the pertechnetate ion(^(99m) TcO₄ ⁻ +^(99m) TcO₄ ⁻) is present in total concentrationsbetween 10⁻⁷ and 10⁻⁹ mole/l.

In addition, the preparation process described by Kaden et al, whichcorresponds to a macroscopic synthesis, cannot be extrapolated to thesynthesis of nitride complexes of ^(99m) Tc on a microscopic scale,where the molar ratios between ^(99m) Tc and the reagents arenecessarily very low. Moreover, the operating procedure described byKaden et al, which requires a separation by distillation, is notsuitable for the preparation of radiopharmaceutical products and is notpractical in a hospital environment, i.e. where the radiopharmaceuticalproducts have to be prepared at the time of their use.

In addition, a process for the preparation of radiopharmaceuticalproducts based on technetium 99m complexes and having a portion(Tc.tbd.N)²⁺ is known, which uses a completely different procedure.Thus, according to this process, which is described by J. Baldas et alin J. Chem. Soc. Dalton Trans. 1981, pp. 1798-1801, Int. J. Appl.Radiat. Ost. 36 1985, pp. 133-139 and in International PatentApplication W085/03063, preparation firstly takes place of a compound offormula R⁺ [^(99m) Tc.tbd.NX₄ ], in which R⁺ is a cation such as sodiumor ammonium and X represents a halogen atom such as Cl or Br and thecompound is then reacted with an appropriate ligand to obtain the ^(99m)Tc complex usable as a radiopharmaceutical product.

The complex R⁺ [^(99m) Tc.tbd.NX₄ ]⁻ is of interest because it is veryhydrolysis-stable and can be used without modification to the Tc.tbd.Npart for substitution reactions with other ligands, which makes itpossible to obtain a wide range of technetium complexes.

The presently known process for the preparation of the intermediatecompound R⁺ [^(99m) TCNX₄ ]⁻ consists of reacting a pertechnetate, suchas sodium pertechnetate with sodium nitride and a halogenated hydracid,such as hydrochloric acid. In order to carry out this reaction dryevaporation takes place of a sodium pertechnetate solution (Tc-99m)using a rotary evaporator and then sodium nitride and concentratedhydrochloric acid are added to the dry residue. Refluxing takes placefor approximately 5 minutes to complete the reduction and destroy thenitride excess and dry evaporation then again takes place using a rotaryevaporator. This gives a residue containing the compound R⁺ (^(99m)Tc.tbd.NCl₄)⁻.

This process is difficult to apply to the production of medical kits,because it takes a long time and involves at least three stages in whicha rotary evaporator is used twice, which is not easy to carry out in anuclear medicine hospital department. Moreover, this process isdifficult to use for the production of medical kits, because thesterility and apyrogeneity of the solutions are difficult to controlthroughout the operations. Therefore the product which is finallyobtained must be sterilized after labelling by Tc-99m, either by passingthrough a sterilizing membrane, or by heat sterilization and it must bechecked for the absence of pyrogen prior to injection into man.

In the case of the preparation of complexes usable in therapy, it isimportant to use a preparation process leading to a high yield ofdesired products.

However, in the case of the product developed by Baldas or Griffith(Coord. Chem. Rev., vol. 8, 1972, pp. 369-396) for the preparation oftechnetium nitride complexes, high complex yields are not possible. Thesame applies with the processes generally used for preparingrhenium-based radiopharmaceutical products.

The present invention specifically relates to a process for thepreparation of nitride complexes of a transition metal chosen from among^(99m) Tc, ¹⁸⁶ Re and ¹⁸⁸ Re usable as radiopharmaceutical products andobviating the disadvantages of the aforementioned process.

The inventive process for the preparation of a radiopharmaceuticalproduct incoporating a nitride complex of a transition metal chosen fromamong ^(99m) Tc, ¹⁸⁶ Re and ¹⁸⁸ Re having a portion M.tbd.N with Mrepresenting the transition metal chosen from among ^(99m) Tc, ¹⁸⁶ Reand ¹⁸⁸ Re, is characterized in that an oxidized compound MO₄ -- of thetransition metal M is reacted with a first ligand chosen from the groupof substituted or unsubstituted, aliphatic and aromatic phosphines andpolyphosphines and a second nitrogenous ligand constituted either by anammonium nitride or a pharmaceutically acceptable metal, or by anitrogenous compound having a >N--N< unit, in which the N's are linkedto hydrogen atoms and/or to monovalent organic groups via a carbon atomor in which one of the N's is linked to the carbon atom of a divalentorganic group via a double bond and the other N is linked to thehydrogen atoms and/or monovalent organic groups via a carbon atom.

According to this process it is possible to easily obtain a nitridecomplex of a transition metal, because it is merely necessary to mix theaforementioned reagents to form the nitride complex.

Generally, the first and second ligands are used in the form ofalcoholic or hydroalcoholic solutions and by the mere addition of thesesolutions to the oxidized compound of the transition metal, e.g. sodiumpertechnetate or sodium perrhenate, a product having the sought nitridecomplex is directly obtained.

Thus, in this case, it is not necessary to firstly carry out the dryevaporation stages for the reagents. It is also unnecessary to sterilizethe product obtained at the end of the reaction, because it issufficient to use a sterile solution of the oxidized compound of thetransition metal. In addition, the inventive process makes it possibleto obtain high yields, which was not the case with the prior artprocesses.

The oxidized compounds of transition metals M used in the invention aresalts of the type MO₄ M', with M' representing an alkali metal orammonium.

In the process of the invention the first phosphine-based ligand acts asa reducing agent for the transition metal and favours the formation ofM.tbd.N, as well as the quantitative fixing of the second nitrogenousligand. Thus, in the absence of the first ligand, it is impossible toobtain by the reaction of the second ligand with the oxidized compoundof the transition metal a complex having a portion M.tbd.N.

Preferably, according to the invention, the reaction between theoxidized compound of the transition metal and the first and secondligands takes place in an aqueous solution.

In order to carry out the reaction, it is possible to aseptically tointroduce the second nitrogenous ligand and the phosphine, preferably inaqueous solution, into a container and then add the requisite quantityof the oxidized compound of the transition metal, e.g. technetium 99mpertechnetate, after having adjusted the pH to an appropriate value byadding an acid or base. It is then possible to carry out the reaction atambient temperature or at a higher temperature between 50° and 100° C.The temperature and pH used are more particularly dependent on thesecond nitrogenous ligand. Normally working takes place at pH valuesbelow 4.

Generally, the molar ratio of the oxidized compound of the transitionmetal to the first nitrogenous ligand is 10⁻⁹ to 10⁻⁴.

The product obtained by this process can be used as it is as aradiopharmaceutical product for therapy or diagnosis.

It can also be used as an intermediate for the production of othernitride complexes usable as radiopharmaceutical products for diagnosisor therapy. In this case, the ligands of the technetium nitride complexpreviously obtained are exchanged by a third organic ligand with anucleophilic group e.g. having a better tropism for certain organs ofthe human body, or by a monoclonal antibody or an antibody fragment.

This exchange reaction can be carried out simultaneously, preferably inan aqueous solution, during the formation of the nitride complex byreacting together the oxidized compound of the transition metal, thefirst ligand, the second nitrogenous ligand and the third organic ligandwith a nucleophilic group, the monoclonal antibody or the antibodyfragment.

It is also possible to carry out this reaction in two stages, namely afirst stage, preferably performed in an aqueous solution, in which theoxidized compound of the transition metal is reacted with the first andsecond ligands and then a second stage, preferably performed in anaqueous solution, in which the product obtained at the end of the firststage is reacted with the third ligand, the monoclonal antibody or theantibody fragment.

However, it is possible to carry out this exchange reaction in analcoholic or hydroalcoholic solution. It is also possible to carry outthe first and second stages in different solutions e.g. the first stagein an aqueous solution and the second stage in an alcoholic orhydroalcoholic solution or vice versa.

The organic ligands with a nucleophilic group used for this exchangereaction can vary greatly. For example, it is possible to use amines,thiols, thioethers, oximes, phosphines and polyfunctional ligands of thepolyaminopolythiol type.

When the reaction is carried out with a monoclonal antibody or anantibody fragment, it is possible to prepare in this way an antibodylabelled by a transition metal. For this reaction, the monoclonalantibody or the antibody fragment used can be activated, e.g. by apretreatment with 2-amino ethane-thiol, or a reducing agent such asdithiothreitol, in order to convert the disulphide bonds into asulphydryl group.

It is possible to use numerous antibody types and in particular thosewhich can be linked to the M.tbd.N portion by sulphur atoms. Examples ofsuch antibodies are anti-ACE antibodies (anti-carcinoembryonic antigen),anti-ovarian carcinoma antibodies (OC125), anti-myosin, anti-fibrin andanticolorectal antibodies.

The antibody or labelled antibody fragment obtained is very interesting,e.g. for the detection of tumours. Thus, after reaction with thetransition metal complex, the monoclonal antibody or antibody fragmentis linked to the transition element such as technetium 99m, but it canreact with the corresponding antigens. Thus, the specificity of theantibody is maintained and the labelled antibody is stable. It is alsopossible to use this labelled antibody for the detection of tumours,because it will be naturally directed towards the corresponding antigenand will reveal the tumours.

In the process of the invention, the choice of the ligands used isimportant, because it conditions the properties of the product obtained.

The first ligand making it possible to obtain the formation of a nitridecomplex is an organic ligand with an electron donor phosphorus atomchosen from among substituted or unsubstituted aliphatic and aromaticphosphines and polyphosphines.

The phosphines which can be used can be in accordance with the formula:##STR1## in which R¹, R² and R³, which can be the same or different,represent a hydrogen atom, an alkyl radical, an aryl radical, an alkoxyradical or an alkyl or aryl radical substituted by a group chosen fromamong the amino, amido, cyano and sulphonate radicals.

Examples of phosphines of this type are triphenyl phosphine, diethylphenyl phosphine, triethyl phosphine, trimethyl phosphine,tris(2-cyanoethyl)-phosphine and sulphonated triphenyl phosphine.Preference is generally given to the use of triaryl phosphines as thetriphenyl phosphine, because they are less oxidizable than the trialkylphosphines.

The polyphosphines which can be used in the invention can comply withthe formulas: ##STR2## in which R¹, R², which can be the same ordifferent, represent a hydrogen atom, an alkyl radical, an aryl radical,an alkoxy radical or an alkyl or aryl radical substituted by a groupchosen from among amino and amido radicals and m is an integer from 1 to4.

Examples of such polyphosphines are bis(dimethyl-1,2-phosphino)-ethaneand bis(diphenyl-1,2-phosphino)-ethane.

As shown hereinbefore, the second ligand can be a nitride of apharmaceutically acceptable metal or ammonium, or a nitrogenous compoundhaving the unit >N--N<.

The nitrides of the pharmaceutically acceptable metals can in particularbe alkali metal nitrides, e.g. sodium nitride.

The nitrogenous compounds having the >N--N< unit can comply with theformula: ##STR3## in which R⁴, R⁵, R⁶ and R⁷, which can be the same ordifferent, represent a hydrogen atom, an alkyl radical, an aryl radical,an alkoxy radical, an alkyl radical substituted by at least one groupchosen from among the hydroxy, carboxy, amino, amido and mercaptoradicals, an aryl radical substituted by at least one group chosen fromamong the halogen atoms and alkoxy, hydroxy, amino and mercapto radicalor amine radical substituted by at least one alkyl radical, a radical inaccordance with the formulas: ##STR4## in R⁸ and R⁹, which can be thesame or different, represent a hydrogen atom, an alkyl radical or anamino radical, a radical of formula: ##STR5## in which R¹⁰ represents ahydrogen atom, an alkyl radical or an aryl radical, a radical of formulaR¹¹ --CO-- with R¹¹ representing an alkyl radical, an alkoxy radical, anaryl radical not substituted or substituted by at least one group chosenfrom among the halogen atoms and the hydroxy radicals, or a radicalderived from a heterocycle which is not substituted or substituted by atleast one group chosen from among the halogen atoms and the hydroxyradical, or in which R⁴ and R⁵ can together form a divalent radical offormula: ##STR6## in which R¹² represents --CH₂ --NH₂, an aryl radicalnot substituted or substituted by at least one group chosen from amongthe halogen atoms and the alkoxy, hydroxy, amino and mercapto radical oramino radical substituted by at least one alkyl radical, or a radicalderived from a heterocycle, which is not substituted or substituted byone or more groups chosen from among halogen atoms and hydroxy, alkoxy,amino and mercapto radicals and amino radicals substituted by at leastone alkyl radical and R¹³ represents a hydrogen atom, an alkyl radicalor an alkyl radical substituted by at least one group chosen from amonghydroxy, carboxy, amino, amido and mercapto radicals and R⁶ and R⁷ havethe meanings given hereinbefore.

These nitrogenous compounds can in particular belong to the group ofhydrazine and its derivatives such as alkylhydrazines, semicarbazides,hydrazides, thiosemicarbazides, carbohydrazides, thiocarbohydrazides,acetohydrazide, hydrazine carboxylates and aminoguanidines; to the groupof dithiocarbazic acid and its derivatives; and to the group of productsobtained by the condensation of the aforementioned compounds withaliphatic or aromatic aldehydes or ketones.

Thus, the second nitrogenous ligand can be dithiocarbazic acid or aderivative thereof in accordance with the formula: ##STR7## in which R¹⁰represents a hydrogen atom, an alkyl radical or an aryl radical and R¹⁴represents a hydrogen atom, an alkyl radical, an aryl radical, an alkoxyradical, an alkyl radical substituted by at least one group chosen fromamong hydroxy, carboxy, amino, amido and mercapto radicals, or an arylradical substituted by at least one group chosen from among the halogenatoms and the alkoxy, hydroxy, amino and mercapto radicals and the aminoradical substituted by at least one alkyl radical.

It can also be a condensation product obtained by the reaction ofdithiocarbazic acid with an aliphatic aldehyde or ketone of formula R¹⁵-CO-R¹⁶. In this case, it complies with the formula: ##STR8## in whichR¹⁰ represents a hydrogen atom, an alkyl radical or an aryl radical, R¹⁴represents a hydrogen atom, an alkyl radical, an aryl radical, an alkoxyradical, an alkyl radical substituted by at least one group chosen fromamong the hydroxy, carboxy, amino, amido and mercapto radicals, or anaryl radical substituted by at least one group chosen from among thehalogen atoms and the alkoxy, hydroxy, amino and mercapto radicals andthe amino radicals substituted by at least one alkyl radical and R¹⁵ andR¹⁶, which can be the same or different, represent a hydrogen atom, analkyl radical or an alkyl radical substituted by at least one groupchosen from among the hydroxy, carboxy, amino, amido and mercaptoradicals.

The dithiocarbazic acid derivative used as the second ligand can also bethe condensation product of dithiocarbazic acid with an aromaticaldehyde or ketone. In this case, the derivative complies with theformula: ##STR9## in which R¹⁰ represents a hydrogen atom, an alkylradical or an aryl radical, R¹⁴ represents a hydrogen atom, an alkylradical, an aryl radical, an alkoxy radical, an alkyl radicalsubstituted by at least one group chosen from among the hydroxy,carboxy, amino, amido and mercapto radicals or an aryl radicalsubstituted by at least one group chosen from among halogen atoms andalkoxy, hydroxy, amino and mercapto radicals and the amino radicalsubstituted by at least one alkyl radical, R¹⁷ represents a hydrogenatom, an alkyl radical, an alkyl radical substituted by at least onegroup chosen from among the hydroxy, carboxy, amino, amido and mercaptoradicals, R¹⁸ represents a hydrogen atom, a halogen atom, an alkoxyradical, an amino radical or an amino radical substituted by at leastone alkyl group, R¹⁹ represents a hydrogen atom, a hydroxy radical or amercapto radical, E represents a carbon atom or a nitrogen atom and n isan integer between 1 and 4, or in which n is equal to 2 and the two R¹⁸are close to one another and together form an aromatic cycle.

It is also possible to use as the second ligand, the product obtained bythe condensation of dithiocarbazic acid with a ketone having a 5 linkheterocycle. In this case, the second ligand is in accordance with theformula: ##STR10## in which R¹⁰ represents a hydrogen atom, an alkylradical or an aryl radical, R¹⁴ represents a hydrogen atom, an alkylradical, an aryl radical, an alkoxy radical, an alkyl radicalsubstituted by at least one group chosen from among the hydroxy,carboxy, amino, amido and mercapto radicals, or an aryl radicalsubstituted by at least one group chosen from among the halogen atomsand the alkoxy, hydroxy, amino and mercapto radicals and the aminoradicals substituted by at least one alkyl radical, R¹⁷ represents ahydrogen atom, an alkyl radical, an alkyl radical substituted by atleast one group chosen from among the hydroxy, carboxy, amino, amido andmercapto radicals, R¹⁸ represents a hydrogen atom, a halogen atom, analkoxy radical, an amino radical, or an amino radical substituted by atleast one alkyl group, G is S or O and p is 1, 2 or 3.

The second ligand can also be hydrazine or a hydrazine derivativecomplying with the formula:

    R.sup.20 --NH--NH--R.sup.21

in which R²⁰ is a hydrogen atom or an alkyl radical and R²¹ is ahydrogen atom or a radical chosen from among the radicals of formula:##STR11## in which R²² and R²³, which can be the same or different,represent a hydrogen atom, an alkyl radical or an amino radical, R²⁴represents an alkyl radical and R²⁵ represents an aryl radical, which isnot substituted or substituted by at least one group chosen from amongthe halogen atoms and the hydroxy radicals or a radical derived from aheterocycle, which is not substituted or substituted by at least onegroup chosen from among the halogen atoms and the hydroxy radicals.

The alkyl and alkoxy radicals used in the ligands described hereinbeforecan be straight or branched radicals and generally have 1 to 3 carbonatoms.

The aryl radicals are radicals derived from a nucleus by elimination ofa hydrogen atom such as phenyl and naphthyl radicals. For example, theradicals derived from heterocyclic nuclei can be furfuryl, pyridyl andthiofurfuryl radicals.

The ligands described hereinbefore are commercial products or can beprepared by conventional processes.

In the process according to the invention where the transition metal istechnetium or rhenium, the nitrogenous ligands used can be monodentate,bidentate or tridentate.

Thus, it would appear that the nitride complex obtained has the squarebased pyramidal structure shown below in the case of Tc: ##STR12## inwhich A represents the phosphine-based ligand and B, C and D representthe nitrogenous ligand or ligands.

In the case of a tridentate nitrogenous ligand, such asS-methyl-beta-N(2-hydroxyphenyl)methylene-dithiocarbazate of formula:##STR13## position B is occupied by one of the nitrogen atoms of thedithiocarbazate, whilst the C and D positions are occupied by the O⁻ andS⁻ atoms of the ionized dithiocarbazate. Therefore the complex has thefollowing structure: ##STR14##

Thus, when using a tridentate nitrogenous ligand, a single complex willbe obtained. However, when using monodentate nitrogenous ligands, it ispossible to have different types of complexes as a function of whetherthe first ligand of the phosphine type occupies one or several positionsA, B, C and D of the complex.

When the complex obtained from the first and second ligands is reactedwith a third organic ligand with a nucleophilic group, it is necessaryfor said third organic ligand to be monodentate, bidentate ortetradentate in the case where the transition metal is Tc. Thus, in thiscase, it is possible to obtain the replacement of the first and secondligands by the third tetradentate ligand. In the case of monodentate orbidentate ligands, several complexes can be prepared, but it is foundthat there is generally a rearrangement of the complexes obtained infavour of the technetium complex having in particular the thrid ligand.

In the invention, the choice of the ligands used is very important,because it in particular conditions the properties of theradiopharmaceutical product obtained. Thus, by choosing a secondnitrogenous ligand with a particular affinity for certain organs withTc-99m, appropriate for scintigraphic examinations, it is possible toprepare a radiopharmaceutical composition directly usable for diagnosis.In this case, it is obviously also necessary for the first and secondligands not to be toxic and to be administrable to man.

Thus, the invention also relates to a kit for the preparation of aradiopharmaceutical product incorporating a nitride complex of ^(99m)Tc, ¹⁸⁶ Re or ¹⁸⁸ Re comprising a first bottle containing the firstligand of the phosphine type and a second bottle containing the secondnitrogenous ligand.

Thus, it is possible to directly prepare from said kit the desiredradiopharmaceutical product in a nuclear medicine hospital department,by mixing the content of the two bottles and by adding thereto e.g. asolution of ammonium or alkali metal pertechnetate. The first and secondligands can be respectively present in the first and second bottles inliquid or lyophilized form.

In certain cases, it is also possible to mix in the same bottle thefirst and second ligands and add at the last moment the solution of theoxidized transition metal compound, e.g. pertechnetate or perrhenate, inorder to prepare the radiopharmaceutical product.

As has been shown hereinbefore, it is also possible to use thetransition metal complex obtained from the first and second ligands asan intermediate for the preparation of another transition metal nitridecomplex by exchange reaction with a third ligand, a monoclonal antibodyor an antibody fragment.

The product obtained at the end of this reaction can also be used as itis as a radiopharmaceutical product for diagnosis or therapy. In thiscase, the kit permitting the preparation of the radiopharmaceuticalproduct can comprise a third bottle containing the third organic ligandwith a nucleophilic group, the monoclonal antibody or the antibodyfragment.

Other features and advantages of the invention can be gathered from thefollowing non-limitative, illustrative examples.

EXAMPLE 1

Into a penicillin type bottle are introduced 0.4 ml of a solutioncontaining 2·10⁻² mole/l (2.5 mg/ml) of S-methyl dithiocarbazate (secondligand) in ethyl alcohol and then 0.2 ml of a 2·10⁻² mole/l (5 mg/ml)triphenyl phosphine solution (first ligand) in ethyl alcohol, as well as0.1 ml of 1N hydrochloric acid. This is followed by the addition of 0.5to 1 ml of sodium pertechnetate solution (Tc-99m) (10⁻⁹ to 10⁻¹¹ mole ofTc) and the reaction is performed at 80° C. for 30 minutes.

Thin layer chromatographic analysis of the product obtained shows thatit is a technetium nitride complex with Tc.tbd.N.

EXAMPLES 2 TO 13

The same operating procedure as in example 1 is followed in order toprepare from the ligands given in table 1, technetium nitride complexesby introducing into the bottle 5·10⁻³ to 1·10⁻² mmole of the secondligand, 4·10⁻³ mmole of the first ligand and 0.1 ml of 1N HCl, followedby the addition of 0.5 to 1 ml of sodium pertechnetate solution.Chromatographic analysis of the products obtained revealed that they arenitride complexes with the portion Tc.tbd.N.

EXAMPLE 14

Into a penicillin type bottle are introduced 0.4 ml of an alcoholicsolution of the second ligand constituted by a 2.5 mg/ml (1.1·10⁻²mole/l) solution of S-methyl-beta-N(2-hydroxyphenyl) methylenedithiocarbazate in ethyl alcohol, 0.2 ml of a 5 mg/l (2·10⁻ 2 mole/l)triphenyl phosphine solution (first ligand) in ethyl alcohol and 0.1 mlof a 1N hydrochloric acid solution.

This is followed by the addition of 0.5 to 1 ml of a sterile sodiumpertechnetate solution (technetium-99m) corresponding to a radioactivitybetween 18 MBq to 3.7 GBq (0.5 to 100 mCi) and the bottle is heated to80° C. for 30 minutes.

Thin layer chromatographic analysis in the inverse Whatman KC 18 phaseusing as the solvent a mixture of methanol, acetonitrile,tetrahydrofuran and 0.5M ammonium acetate (proportions 3:3:2:2) revealsthe appearance of a pure product with a Rf of 0.35 and confirms thepresence of Tc.tbd.N.

EXAMPLES 15 TO 22

The operating procedure of example 14 is repeated with the first andsecond ligands of table 2 introducing into the bottle 1·10⁻ 2 to 3·10⁻ 3mmole of the second ligand. 4·10⁻ 3 mmole of the first ligand and 0.1 mlof 1N HCl and finally adding 0.5 to 1 ml of sodium pertechnetatesolution Tc-99m. At the end of the operation, the product obtainedundergoes thin layer chromatography showing that the complex has theportion Tc.tbd.N and that the phosphine forms an integral part of thecomplex obtained.

EXAMPLE 23

The operating procedure of example 1 is followed, but using as thesecond ligand 4-methyl-3-thiosemicarbazide of formula: ##STR15##

By chromatographic analysis it is established that the complex obtainedis indeed a technetium nitride complex and comprises triphenylphosphine.

EXAMPLE 24

This example adopts the same operating procedure as in example 14, butusing as the second ligand the aminoacetone semicarbazone of formula:##STR16##

Thin layer chromatography reveals that the complex obtained is indeed atechnetium nitride complex.

EXAMPLE 25

Into a penicillin type bottle are introduced 1 ml of a 5·10⁻³ mole/lsolution of alpha-N-methyl-S-methyl-beta-N-(2-hydroxyphenyl)-methylenedithiocarbazate in ethyl alcohol, 0.2 ml of a 6·10⁻³ mole/l solution ofbis(dimethyl-1,2-phosphino)-ethane of formula:

    (CH.sub.3).sub.2 P--CH.sub.2 --CH.sub.2 --P (CH.sub.3).sub.2

and 0.1 ml of 1N hydrochloric acid. This is followed by the addition of0.5 ml of a sterile sodium pertechnetate solution (Tc-99m) and thebottle is heated at 80° C. for 30 minutes. This gives a technetiumnitride complex having the first diphosphine-based ligand.

EXAMPLE 26

The operating procedure of example 25 is adopted, but use is made of a5·10⁻³ mole/l solution of bis(diphenyl-1,2-phosphine)-ethane and a5·10⁻³ mole/l solution ofalpha-N-methyl-S-methyl-beta-N(2-hydroxyphenyl)-methylenedithiocarbazate. Once again a technetium nitride complex is obtainedhaving the diphosphine ligand.

EXAMPLE 27

In this example, a rhenium 186 complex is prepared by introducing into apenicillin type bottle 7 mmole of triphenyl phosphine and 2 mmole ofalpha-N-methyl-S-methyl-beta-N-(2-hydroxyphenyl)-methylenedithiocarbazate in alcoholic solution and 5 mmole of 1N hydrochloricacid. This is followed by the addition of 1 mmole of sodium perrhenateand the reaction is carried out at 40° C. for 30 minutes. This gives arhenium nitride complex with a yield higher than 90%.

In the following examples, use is made of the technetium nitridecomplexes obtained in the preceding examples for forming othertechnetium complexes usable as diagnosis products.

EXAMPLE 28

This example uses the product obtained in example 14 for preparinganother technetium complex with a third ligand constituted by1,1'-(1,2-ethane diyl-diimino)-bis (2-methyl-2-propane thiol) offormula: ##STR17##

To the content of the bottle obtained in example 14 is added 0.2 ml of a4·10⁻² mole/l 1,1'-(1,2-ethane diyldiimino)-bis(2-methyl-2-propanethiol) solution in ethanol. The pH is brought to 9.5 by adding 0.5 ml ofa 0.5M dicarbonate/carbonate buffer solution and the bottle is heated to80° C. for 30 minutes.

The product obtained is subject to thin layer chromatography usingsilica gel and a solvent formed from ethanol-chloroform-benzene (2:2:1).The locations of the chromatographic spots correspond to a technetiumnitride complex with the portion Tc.tbd.N.

COMPARATIVE EXAMPLE 1

In this example reaction takes place of a 1,1'-(1,2-ethanediyl-diimino)-bis-(2-methyl-2-propane thiol) solution with sodiumpertechnetate (Tc-99m) in the presence of stannous chloride. This givesan oxotechnetium diaminodithiolate analyzed by thin layer chromatographyunder the same conditions as the product obtained in example 27. Thelocation of the chromatographic spots for this Tc complex containing(TcO)³⁺ differs from that obtained in example 26 with the nitridecomplex.

EXAMPLES 29 TO 36

The same operating procedure as in example 28 is adopted for thepreparation of other technetium nitride complexes from those productsobtained in examples 1, 2 and 16 to 21 using as the third ligand1,1'-(1,2-ethane diyl-diimino)-bis-(2-methyl-2-propane thiol). In allcases a technetium nitride complex having said third ligand is obtained.

EXAMPLE 37

The operating procedure of example 28 is used for preparing a noveltechnetium complex from the product obtained in example 1, but using asthe third ligand a 6·10⁻² mole/l tetraazaundecane solution of formula:##STR18##

This gives a novel technetium nitride complex having tetraazaundecane asthe ligand. The purity of the product is tested by thin layerchromatography using cellulose and a solvent based on ethanol-0.15Mammonium acetate (ratio 4:3).

EXAMPLES 38 TO 45

These examples follow the same operating procedure as in example 37adding to the product obtained in examples 2, 14 and 16 to 21, 0.2 ml ofa 6·10⁻² mole/l tetraazaundecane solution. In all cases a technetiumnitride complex is obtained having the tetraazaundecane ligand.

EXAMPLE 46

To the content of the bottle obtained in example 16 is added 0.1 ml of a6·10⁻² mole/l (13 mg/ml) solution of bis(1,2-dimethyl phosphine)-ethanedihydrochloride (DMPE). The pH is brought to 10 by adding 0.5 ml of a0.5 mole/l carbonate/dicarbonate buffer solution and the reaction iscarried out at 80° C. for 30 minutes.

The product obtained is analyzed by thin layer chromatography(cellulose; solvent: ethanol-0.15M ammonium acetate, 4:3). It is atechnetium nitride complex with the third ligand. Thus, thechromatographic spots obtained with this complex are different fromthose obtained with the known technetium complexes having the formula:

    .sup.99m TcCl.sub.2 DMPE.sub.2 + and .sup.99m TcO.sub.2 DMPE.sub.2 +

EXAMPLE 47 Preparation of a ^(99m) Tc.tbd.N complex containing8-mercapto quinoline a) Preparation of the intermediate

Into a penicillin type bottle are introduced 0.2 ml of a solutioncontaining 7.7·10⁻² mole/l (5 mg/ml) of sodium nitride in water and then0.5 ml of a solution containing 5.2·10⁻³ mole/l (1 mg/ml) oftris(2-cyanoethyl)-phosphine in water. This is followed by the additionof 0.5 to 5 ml of a sodium pertechnetate solution (^(99m) Tc) and thereaction is performed at 80° C. for 30 minutes or 100° C. for 15minutes.

b) Preparation of the final complex

To the content of the bottle obtained in stage a), or to a fractionthereof, area added 0.3 ml of a 0.5 mole/l sodium bicarbonate-carbonatebuffer solution at pH 9 and 0.4 ml of a solution containing 5·10⁻²mole/l of 8-mercapto quinoline hydrochloride (10 mg/ml) in ethanol. Thereaction is performed for 15 minutes at 100° C., 30 minutes at 80° C. or60 minutes at ambient temperature.

The radiochemical purity of the product obtained is tested by thin layerchromatography using a silica gel and a mixture of ethanol, chloroform,toluene and 0.5M ammonium acetate in the proportion 6:3:3:1. The productobtained has a Rf of 0.95, whereas ^(99m) TcO⁻⁴ has a Rf of 0.5. Theradiochemical purity is equal to or better than 95%.

EXAMPLE 48 Preparation of an antibody labelled with the intermediatecomplex Tc.tbd.N

d) Preparation of the intermediate.

Into a penicillin type bottle are introduced 0.4 ml of a solutioncontaining 2·10⁻² mole/l (2.7 mg/ml) of S-methyl-N-methyldithiocarbazate in water and then 0.5 ml of a solution containing5.2·10⁻³ mole/l of tris(2-cyanoethyl)-phosphine in water and 0.1 ml of1N hydrochloric acid. This is followed by the addition of 0.5 to 5 ml ofa sodium pertechnetate solution (^(99m) Tc) and the reaction isperformed at 80° C. for 30 minutes or at 100° C. for 15 minutes.

b) Preparation of the labelled antibody.

To the content of the bottle obtained in stage a) adjusted to pH 7, orto a fraction thereof, is added 1 mg of whole monoclonal anti-ACEantibody (anti-carcinoembryonic antigen) pretreated by mercapto ethanolamine in order to activate the sulphydryl groups (whole activatedantibody) in a 0.1M phosphate buffer solution at pH 7. The reactiontakes 30 minutes at 35° C.

The radiochemical purity is tested by carrying out chromatography byfiltration on gel on a type G 3000 SW (0.75×30 cm) TSK column using a0.1M phosphate buffer at pH 7 and at a flowrate of 1 ml/minute. Theradioactivity and absorbance of the sample are registeredsimultaneously. 95% of the radioactivity is eluted between 7 and 7.8 mland the detectable quantity of ^(99m) TcO⁻⁴ at 12 ml is below 5%.

EXAMPLES 49 to 55

In these examples testing takes place of the properties of the complexesobtained in examples 2, 14, 17, 21, 28, 37 and 47 by determining theirbiodistribution in male Sprague Dawley rats weighing 200×20 g. In thiscase, the pentobarbital-anesthetized rats, are injected with a radiationdose of 3.7 to 10 KBq (1 to 2.7 μCi). The animals are sacrificed 5minutes following the injection of the product. The organs are removed,washed and their radioactivity measured by means of a scintillationcounter.

The results obtained are given in table 3 and are expressed as apercentage of the injected radioactivity found in the organ followingsampling and counting. The values given in each box of the tablerepresent the mean value of three experiments.

                                      TABLE 1                                     __________________________________________________________________________                ##STR19##                                                         1st ligand (5 · 10.sup.-3 to 1 · 10.sup.-2 mmole)           EX 4 · 10.sup.-3 mmole                                                          NAME          R.sup.4                                                                          R.sup.5                                           __________________________________________________________________________    1  triphenyl phosphine                                                                   S-methyl dithiocarbazate                                                                    H                                                                                 ##STR20##                                        2  triphenyl phosphine                                                                   S-methyl N-methyl dithiocarbazate                                                           CH.sub.3                                                                          ##STR21##                                        3  triphenyl                                                                             hydrazine in  H  H                                                    phosphine                                                                             dihydrochloride                                                               form                                                                          NH.sub.2NH.sub.2, 2HCl                                             4  triphenyl phosphine                                                                   semicarbazide in hydrochloride form                                                         H                                                                                 ##STR22##                                                    ##STR23##                                                         5  triphenyl phosphine                                                                   thiosemicarbazide                                                                           H                                                                                 ##STR24##                                        6  triphenyl phosphine                                                                   4-methyl-3-thio- semicarbazide                                                              H                                                                                 ##STR25##                                        7  triphenyl phosphine                                                                   carbohydrazide                                                                              H                                                                                 ##STR26##                                        8  triphenyl phosphine                                                                   thiocarbohydrazide                                                                          H                                                                                 ##STR27##                                        9  triphenyl phosphine                                                                   acetohydrazide                                                                              H                                                                                 ##STR28##                                        10 triphenyl phosphine                                                                   methyl hydrazine carboxylate                                                                H                                                                                 ##STR29##                                        11 triphenyl phosphine                                                                   furoyl-2-hydrazide                                                                          H                                                                                 ##STR30##                                        12 triphenyl phosphine                                                                   Salicyloyl hydra- zide                                                                      H                                                                                 ##STR31##                                        13 triphenyl phosphine                                                                   aminoguanidine                                                                              H                                                                                 ##STR32##                                        __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________               ##STR33##                                                          EX 1st ligand                                                                           NAME        R.sup.4                                                                          R.sup.5                                                                              R.sup.11                                      __________________________________________________________________________    14 triphenyl phosphine                                                                  S-methyl β-N(2-hy- droxyphenyl)methylene dithiocarbazate                             H                                                                                 ##STR34##                                                                            ##STR35##                                    15 triphenyl                                                                            α-N-methyl S-methyl                                                                 CH.sub.3                                                                         "      "                                                phosphine                                                                            β-N(2-hydroxyphenyl)                                                     methylene dithiocar-                                                          bazate                                                              16 triphenyl phosphine                                                                  α,N-methyl-S-methyl β-N pyridylmethylene dithiocarbaz              ate         "  "                                                                                     ##STR36##                                    17 diethyl phenyl phosphine                                                             S-methyl β, N(2-hy- drophenyl)methylene dithiocarbazate                              H  "                                                                                     ##STR37##                                    18 triphenyl phosphine                                                                  S-methyl-β, N(2,5- dihydroxy-phenyl) methylene dithiocar-                bazate      H                                                                                 ##STR38##                                                                            ##STR39##                                    19 diethyl                                                                              S-methyl-β, N(2,5-                                                                   "  "      "                                                phenyl dihydroxy-phenyl)                                                      phosphine                                                                            methylene dithiocar-                                                          bazate                                                              20 triethyl                                                                             S-methyl-β, N(2,5-                                                                   "  "      "                                                phosphine                                                                            dihydroxy-phenyl)                                                             methylene dithiocar-                                                          bazate                                                              21 trimethyl                                                                            S-methyl-β, N(2,5-                                                                   "  "      "                                                phosphine                                                                            dihydroxy-phenyl)                                                             methylene dithiocar-                                                          bazate                                                              22 triphenyl phosphine trisulphonate                                                    α-N-methyl S-methyl β-N(2-hydroxyphenyl) methylene                 dithiocar- bazate                                                                         CH.sub.3                                                                         "                                                                                     ##STR40##                                    __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    Ex. 49     Ex. 50                                                                              Ex. 51                                                                              Ex. 52                                                                              Ex. 53                                                                              Ex. 54                                                                              Ex. 55                               __________________________________________________________________________    Whole                                                                              Complex of                                                                          Complex of                                                                          Complex of                                                                          Complex of                                                                          Complex of                                                                          Complex of                                                                          Complex of                           organs                                                                             example 2                                                                           example 14                                                                          example 17                                                                          example 21                                                                          example 28                                                                          example 37                                                                          example 47                           Liver                                                                              19.71 32.41 35.64 20.23 12.42 13.63 7.30                                 Kidneys                                                                            7.02  0.80  2.09  4.54  14.70 19.61 0.87                                 Lungs                                                                              5.54  2.89  2.07  2.86  1.11  0.84  12.64                                Brain                                                                              0.22  0.06  0.15  0.56  0.08  0.06  0.19                                 Heart                                                                              0.82  0.48  0.90  0.67  0.35  0.24  0.23                                 Blood                                                                              18.03 32.22 17.58 15.06 7.56  10.38 0.84                                 __________________________________________________________________________

We claim:
 1. A process for the preparation of a radiopharmaceuticalproduct incorporating a nitride complex of a transition metal selectedfrom the group consisting of ^(99m) Tc, ¹⁸⁶ Re and ¹⁸⁸ Re, having aportion M.tbd.N with M representing the transition metal, characterizedin that about 10⁹ -10¹¹ moles of an oxidized compound, MO₄ ⁻, of thetransition metal M is reacted with a first ligand selected from thegroup consisting of substituted or unsubstituted aliphatic and aromaticphosphines and polyphosphines, and a second nitrogenous ligandconsisting of either an ammonium nitride or a pharmaceuticallyacceptable metal nitride, or of a nitrogenous compound having a >N--N<unit, in which the Ns are linked with the hydrogen atoms and/ormonovalent organic groups via a carbon atom, or in which one of the endsis linked with the carbon atom of a divalent organic group via a doublebond and the other N is linked with the hydrogen atoms and/or monovalentorganic groups via a carbon atom.
 2. A process according to claim 1,characterized in that the reaction is performed in an aqueous solution.3. A process according to claim 1 wherein the radiopharmaceuticalproduced is sterile and apyrogenic.
 4. A process as claimed in claim 1wherein 0.5 to 100 mCi of transition metal is reacted with a first and asecond ligand.
 5. A process according to claim 1, wherein 10⁻⁹ -10⁻¹¹mole of MO₄ ⁻ is reacted with a first and a second ligand.
 6. A processas claimed in claim 5 wherein the molar ratio of MO₄ ⁻ to thenitrogenous ligand is from 10⁻⁹ to 10⁻⁴.
 7. A process according to claim1, consisting of:1) adding solutions of the first and the second ligandsto a container, 2) adjusting the pH of the solution obtained in 1) to avalue below 4, and 3) adding 10⁻⁹ -10⁻¹¹ moles of the oxidized compoundof the transition metal to the solution obtained in 2) above.
 8. Aprocess according to claim 1, characterized in that the oxidizedcompound of the transition metal is a -99m pertechnetate of alkali metalor ammonium.
 9. A process according to claim 1, characterized in thatthe oxidized compound of the transition metal is -186 or -188 perrhenateof alkali metal or ammonium.
 10. A process according to claim 1,characterized in that the first ligand is a phosphine complying with theformula: ##STR41## in which R¹, R² and R³, which can be the same ordifferent, represent a hydrogen atom, a C₁ -C₃ alkyl radical, a phenylradical, a naphthyl radical, a C₁ -C₃ alkoxy radical or said C₁ -C₃alkyl, phenyl or naphthyl radical substituted by a group selected fromthe group consisting of amino, amido, cyano and sulphonate radicals. 11.A process according to claim 10, characterized in that the first ligandis a phosphine selected from the group consisting of triphenylphosphine, diethyl phenyl phosphine, triethyl phosphine, trimethylphosphine and tris(2-cyanoethyl)-phosphine.
 12. A according to claim 1,characterized in that the first ligand is a polyphosphine complying withone of the formulas: ##STR42## in which R¹, and R², which can be thesame or different, represent a hydrogen atom, a C₁ -C₃ alkyl radical, aphenyl radical, a naphthyl radical, a C₁ -C₃ alkoxy radical or said C₁-C₃ alkyl, phenyl or naphthyl radical substituted by a group selectedfrom the group consisting of amino and amido radicals and m is aninteger between 1 and
 4. 13. A process according to claim 1,characterized in that the second ligand is a nitrogenous compoundcomplying with the formula: ##STR43## in which R⁴, R⁵, R⁶ and R⁷, whichcan be the same or different, represent a hydrogen atom, a C₁ -C₃ alkylradical, a phenyl radical, a naphthyl radical, a C₁ -C₃ alkoxy radical,said C₁ -C₃ alkyl radical substituted by at least one group selectedfrom the group consisting of hydroxy, carboxy, amino, amido and mercaptoradicals, said phenyl or naphthyl radical substituted by at least onegroup selected from the group consisting of halogen atoms and alkoxy,hydroxy, amino and mercapto radicals an amine radical substituted by atleast one C₁ -C₃ alkyl radical, a radical in accordance with theformulas: ##STR44## in which R⁸ and R⁹, which can be the same ordifferent, represent a hydrogen atom, a C₁ -C₃ alkyl radical or an aminoradical, a radical of formula: ##STR45## in which R¹⁰ represents ahydrogen atom, a C₁ -C₃ alkyl radical, a phenyl radical or a naphthylradical, a radical of formula R¹¹ --CO-- with R¹¹ representing a C₁ -C₃alkyl radical, a C₁ -C₃ alkoxy radical, a phenyl or naphthyl radical notsubstituted or substituted by at least one group selected from the groupconsisting of halogen atoms and hydroxy radicals, or a radical derivedfrom a heterocycle and selected from the group consisting of furfuryl,pyridyl and thiofuryl radicals which are not substituted or aresubstituted by at least one group selected from the group consisting ofhalogen atoms and hydroxy radicals, or in which R⁴ and can together forma divalent radical of formula: ##STR46## in which R¹² represents --CH₂--NH₂, a phenyl or naphthyl radical not substituted or substituted by atleast one group selected from the group consisting of halogen atoms andC₁ -C₃ alkoxy, hydroxy, amino and mercapto radicals or an amino radicalsubstituted by at least one C₁ -C₃ alkyl radical, or a radical derivedfrom a heterocycle and selected from the group consisting of furfuryl,pyridyl and thiofuryl radicals, which is not substituted or issubstituted by one or more groups selected from the group consisting ofhalogen atoms and hydroxy, C₁ -C₃ alkoxy, amino and mercapto radicalsand amino radical radicals substituted by at least one C₁ -C₃ alkylradical and R¹³ represents a hydrogen atom, a C₁ -C₃ alkyl radical or aC₁ -C₃ alkyl radical substituted by at least one group selected from thegroup consisting of hydroxy, carboxy, amino, amido and mercapto radicalsand R⁶ and R⁶ have the meaning given hereinbefore.
 14. A processaccording to claim 1, characterized in that the second ligand is adithiocarbazic acid or a derivative thereof complying with the formula:##STR47## in which R¹⁰ represents a hydrogen atom, an alkyl radical oran aryl radical and R¹⁴ represents a hydrogen atom, an alkyl radical, anaryl radical, an alkoxy radical, an alkyl radical substituted by atleast one group selected from the group consisting of hydroxy, carboxy,amino, amido and mercapto radicals, or an aryl radical substituted by atleast one group selected from the group consisting of halogen atoms andalkoxy, hydroxy, amino and mercapto radicals and an amino radicalsubstituted by at least one alkyl radical wherein said alkyl and alkoxyradicals have from 1 to 3 carbon atoms and wherein said aryl radical isselected from the group consisting of phenyl and naphthyl radicals. 15.A process according to claim 1, characterized in that the second ligandis a condensation product of dithiocarbazic acid in accordance with theformula: ##STR48## in which R¹⁰ represents a hydrogen atom, an alkylradical or an aryl radical and R¹⁴ represents a hydrogen atom, an alkylradical, an aryl radical, an alkoxy radical, an alkyl radicalsubstituted by at least one group selected from the group consisting ofhydroxy, carboxy, amino, amido and mercapto radicals, or an aryl radicalsubstituted by at least one group selected from the group consisting ofhalogen atoms and alkoxy, hydroxy, amino and mercapto radicals and aminoradical substituted by at least one alkyl radical and amino radicalssubstituted by at least one alkyl radical and R¹⁵ and R¹⁶, which can bethe same or different, represent a hydrogen atom, an alkyl radical or analkyl radical substituted by at least one group selected from the groupconsisting of hydroxy, carboxy, amino, amido and mercapto radicalswherein said alkyl and alkoxy radicals have from 1 to 3 carbon atoms andwherein said aryl radical is selected from the group consisting ofphenyl and naphthyl radicals.
 16. A process according to claim 1,characterized in that the second ligand is a condensation product ofdithiocarbazic acid in accordance with the formula: ##STR49## in whichR¹⁰ represents a hydrogen atom, an alkyl radical or an aryl radical, R¹⁴represents a hydrogen atom, an alkyl radical, an aryl radical, an alkoxyradical, an alkyl radical substituted by at least one group selectedfrom the group consisting of hydroxy, carboxy, amino, amido and mercaptoradicals, or an aryl radical substituted by at least one group selectedfrom the group consisting of halogen atoms and alkoxy, hydroxy, aminoand mercapto radical, and an amino radical substituted by at least onealkyl radical, R¹⁷ represents a hydrogen atom, an alkyl radical, analkyl radical substituted by at least one group selected from the groupconsisting of hydroxy, carboxy, amino, amido and mercapto radicals, R¹⁸represents a hydrogen atom, a halogen atom, an alkoxy radical, an aminoradical or an amino radical substituted by at least one alkyl group, R¹⁹represents a hydrogen atom, a hydroxy radical or a mercapto radical, Erepresents a carbon atom or a nitrogen atom and n is an integer between1 and 4, or in which n is equal to 2 and the two R¹⁸ together form anaromatic cycle wherein said alkyl and alkoxy radicals have from 1 to 3carbon atoms and wherein said aryl radical is selected from the groupconsisting of phenyl and naphthyl radicals.
 17. A process accordingclaim 1, characterized in that the second ligand is a condensationproduct of dithiocarbazic acid in accordance with the formula: ##STR50##which R¹⁰ represents a hydrogen atom, an alkyl radical or a arylradical, R¹⁴ represents a hydrogen atom, an alkyl radical, an arylradical, an alkoxy radical, an alkyl radical substituted by at least onegroup selected from the group consisting of hydroxy, carboxy, aminoamido and mercapto radicals, or an aryl radical substituted by at leastone group selected from the group consisting of halogen atoms andalkoxy, hydroxy, amino and mercapto radicals and amino radicalssubstituted by at least one alkyl radical, R¹⁷ represents a hydrogenatom, an alkyl radical, an alkyl radical substituted by at least onegroup selected from the group consisting of hydroxy, carboxy, amino,amido and mercapto radicals, R¹⁸ represents a hydrogen atom, a halogenatom, an alkoxy radical, an amino radical, or an amino radicalsubstituted by at least one alkyl group, G is S or O and p is 1, 2 or 3wherein said alkyl and alkoxy radicals have from 1 to 3 carbon atoms andwherein said aryl radical is selected from the group consisting ofphenyl and naphthyl radicals.
 18. A process according to claim 1,characterized in that the second ligand is hydrazine or a hydrazinederivative complying with the formula:

    R.sup.20 --NH--NH--R.sup.21

in which R²⁰ is a hydrogen atom or an alkyl radical and R²¹ is ahydrogen atom or a radical chosen from among the radicals of formula:##STR51## in which R²² and R²³, which can be the same or different,represent a hydrogen atom, an alkyl radical or an amino radical, R²⁴represents an alkyl radical and R²⁵ represents an aryl radical which isnot substituted or which is substituted by at least one group selectedfrom the group consisting of halogen atoms and hydroxy radicals or afurfuryl, pyridyl or thiofurfuryl radical which is not substituted or issubstituted by at least one group selected from the group consisting ofhalogen atoms and hydroxy radicals wherein said alkyl and alkoxyradicals have from 1 to 3 carbon atoms and wherein said aryl radical isselected from the group consisting of phenyl and naphthyl radicals. 19.A process according to claim 1, characterized in that the second ligandis selected from the group consisting ofS-methyl-beta-N(2-hydroxyphenyl) methylene dithiocarbazate,S-methyldithiocarbazate, S-methyl N-methyldithiocarbazate,alpha-N-methyl-S-methyl-beta-N-pyridylmethylene dithiocarbazate,S-methyl-beta-N-(2,5-dihydroxyphenyl) methylene dithiocarbazate,alpha-N-methyl-S-methyl-N(2-hydroxyphenyl) methylene dithiocarbazate,hydrazine, semicarbazide, thiosemicarbazide,1-methyl-3-thiosemicarbazide, 4-methyl-3-thiosemicarbazide,aminoacetonesemicarbazone, carbohydrazide, thiocarbohydrazide,aceto-hydrazide, methylhydrazinecarboxylate, 2-furoyl hydrazide,salicyloyl hydrazide, aminoguanidine and sodium nitride.
 20. A processfor the preparation of a radiopharmaceutical product incorporating anitride complex of a transition metal selected from the group consistingof ^(99m) Tc, ¹⁸⁶ Re and ¹⁸⁸ Re, having a portion M.tbd.N with Mrepresenting the transition metal, characterized in that an oxidizedcompound, MO₄ ⁻, of the transition metal M is reacted with a firstligand selected from the group consisting of substituted orunsubstituted aliphatic and aromatic phosphines and polyphosphines, anda second nitrogenous ligand consisting of either an ammonium nitride ora pharmaceutically acceptable metal nitride, or of a nitrogenouscompound having a >N-N< unit, in which the Ns are linked with thehydrogen atoms and/or monovalent organic groups via a carbon atom, or inwhich one of the ends is linked with the carbon atom of a divalentorganic group via a double bond and the other N is linked with thehydrogen atoms and/or monovalent organic groups via a carbon atom,wherein the molar ratio of MO₄ ⁻ to the nitrogenous ligand is from about10⁻⁹ to about 10⁻⁴.
 21. A process as claimed in claim 20 wherein themolar ratio of MO₄ ⁻ to the nitrogenous ligand is from 10⁻⁹ to 10⁻⁴. 22.A process for the preparation of a radiopharmaceutical productincorporating a nitride complex of a transition metal selected from thegroup consisting of ^(99m) Tc, ¹⁸⁶ Re and ¹⁸⁸ Re, having a portionM.tbd.N with M representing the transition metal, characterized in thatan oxidized compound, MO₄ ⁻, of the transition metal M is reacted with afirst ligand selected from the group consisting of substituted orunsubstituted aliphatic and aromatic phosphines and polyphosphines and asecond nitrogenous ligand characterized in that the second nitrogenousligand is an alkali metal nitride.